| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1997: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
Cancer in the oral and maxillofacial region is characterized that primary tumors of the oral cavity are frequently adjacent to bony structures. Bone destruction usually extends the area of surgical excision and develops the need for bone resection, leading to cosmetic and functional disturbance. The prevention of the osteolytic bone resorption may reduce these clinically important issues. Angiogenesis inhibitor TNP-470, 6-O-(N-chloroacetyl-carbamoyl)-fumagillol, semisynthetic analogue of fumagillin, has strong inhibitory activities against in vivo tumor growth and metastasis in a wide variety of tumors. However, it is still unknown whether this agent inhibits osteolytic lesions induced by cancer or not. In the present study, we investigated the mechanism of angiogenesis inhibitor, tnp-470 on the role of bone metabolism and clinical approach for human oral cancer jaw invasion in nude mice model.
1.Mechanism of TNP-470 on bone metabolism : In a murine bone marrow culture under 1, 25-dihyd
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roxyvitamin D3 in which mature. functional osteoclasts formed in vitro, TNP-470 significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP) positive multinucleated osteoclast like cells. And also, TNP-470 dose-dependently inhibited the release of Ca from calvaria organ culture stimulated by Vit. D3. However it did not have a cytotoxic activity on the release of LDH and CPK from cultured bone marrow culture system.
2.Effects of TNP-470 for the osteolytic lesions in animal models
1)Daily injections of IL-1beta over the calvariae of nude mice induced a severe bone resorption and stimulated the local proliferation of the periosteal cells as compared to the calvaria not exposed to IL-1beta). Osteoclasts were present along the resorption surface of bone from a mouse treated with IL-1beta. In contrast, treatment with TNP-470 significantly inhibited the bone resorption stimulated with IL-1beta
2)TNP-470 dose-dependently inhibited the serum-Ca on hypercalcemia in mouse model induce by the injection of IL-1 and PTHrP.from calvaria organ culture stimulated by Vit. D3.
3)TNP-470 inhibited the progression of tumor invasion in jaw and the osteolytic bone metastasis in intracardiac injection model.
These data suggested that TNP-470 inhibited bone metastasis through not only anti-tumor action by its angiogenesis inhibition but also by the inhibition of osteoclastic bone resorption. Our results indicate that TNP-470 should be a potentially beneficial drug to be used in the treatment of osteolytic metastasis.(376). Less
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